Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly

Summary

Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly (MONDO:0030785) is a disease caused by PIDD1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PIDD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly
Mondo ID	MONDO:0030785
OMIM	619827
DOID	DOID:0081234
UMLS	C5676961
MedGen	1808159
GARD	0025637
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly · MRT75

Data availability: 28 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

28 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 8 pathogenic, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686875	NM_145886.4(PIDD1):c.2275-1G>A	PIDD1	Pathogenic	no assertion criteria provided
1686876	NM_145886.4(PIDD1):c.2443C>T (p.Arg815Trp)	PIDD1	Pathogenic	no assertion criteria provided
1686877	NM_145886.4(PIDD1):c.2584C>T (p.Arg862Trp)	PIDD1	Pathogenic	criteria provided, single submitter
1686878	NM_145886.4(PIDD1):c.2116_2120del (p.Val706fs)	PIDD1	Pathogenic	no assertion criteria provided
1686879	NM_145886.4(PIDD1):c.1804_1805del (p.Gly602fs)	PIDD1	Pathogenic	no assertion criteria provided
2430140	NM_145886.4(PIDD1):c.1909C>T (p.Arg637Ter)	PIDD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366637	NM_145886.4(PIDD1):c.1819del (p.Ala607fs)	PIDD1	Pathogenic	criteria provided, single submitter
4056722	NM_145886.4(PIDD1):c.1917+1G>T	PIDD1	Pathogenic	criteria provided, single submitter
929836	NM_145886.4(PIDD1):c.2587C>T (p.Gln863Ter)	PIDD1	Pathogenic	no assertion criteria provided
3254685	NM_145886.4(PIDD1):c.296-1G>A	PIDD1	Likely pathogenic	criteria provided, single submitter
3370294	NM_145886.4(PIDD1):c.1302+1G>A	PIDD1	Likely pathogenic	criteria provided, single submitter
4056723	NM_145886.4(PIDD1):c.2214_2241del (p.Ala739fs)	PIDD1	Likely pathogenic	criteria provided, single submitter
1333713	NM_145886.4(PIDD1):c.2042-2A>G	PIDD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2472051	NM_145886.4(PIDD1):c.308G>A (p.Arg103Gln)	PIDD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2581475	NM_145886.4(PIDD1):c.202_203del (p.Arg68fs)	PIDD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664234	NM_145886.4(PIDD1):c.2044C>T (p.Arg682Cys)	PIDD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4073693	NM_145886.4(PIDD1):c.[2116G>A];[2585G>C]		Uncertain significance	criteria provided, single submitter
3065217	NM_145886.4(PIDD1):c.2017G>C (p.Glu673Gln)	PIDD1	Uncertain significance	criteria provided, single submitter
3067912	NM_145886.4(PIDD1):c.1303-10_1303-9insT	PIDD1	Uncertain significance	criteria provided, single submitter
3236566	NM_145886.4(PIDD1):c.744C>G (p.His248Gln)	PIDD1	Uncertain significance	criteria provided, single submitter
3236567	NM_145886.4(PIDD1):c.76G>A (p.Gly26Arg)	PIDD1	Uncertain significance	criteria provided, single submitter
3254686	NM_145886.4(PIDD1):c.277C>T (p.Arg93Cys)	PIDD1	Uncertain significance	criteria provided, single submitter
3377544	NM_145886.4(PIDD1):c.1019G>A (p.Gly340Asp)	PIDD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377545	NM_145886.4(PIDD1):c.2393G>A (p.Arg798His)	PIDD1	Uncertain significance	criteria provided, single submitter
3600395	NM_145886.4(PIDD1):c.2605G>T (p.Val869Leu)	PIDD1	Uncertain significance	criteria provided, single submitter
3767149	NM_145886.4(PIDD1):c.793C>T (p.Leu265Phe)	PIDD1	Uncertain significance	criteria provided, single submitter
4278267	NM_145886.4(PIDD1):c.1813C>T (p.Arg605Trp)	PIDD1	Uncertain significance	criteria provided, single submitter
720379	NM_145886.4(PIDD1):c.2042-8T>C	PIDD1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PIDD1	Strong	Autosomal recessive	intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly	2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIDD1	HGNC:16491	ENSG00000177595	C0HMD6	PIDD1 alternative open reading frame protein	gencc,clinvar

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIDD1	Protease	yes		Death_dom, ZU5_dom, Leu-rich_rpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right hemisphere of cerebellum	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIDD1	189	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIDD1	4

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIDD1	C0HMD6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TP53 Regulates Transcription of Caspase Activators and Caspases	1	951.7×	0.001	PIDD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein autoprocessing	1	648.1×	0.007	PIDD1
regulation of canonical NF-kappaB signal transduction	1	481.5×	0.007	PIDD1
extrinsic apoptotic signaling pathway via death domain receptors	1	401.2×	0.007	PIDD1
DNA damage response, signal transduction by p53 class mediator	1	358.6×	0.007	PIDD1
positive regulation of apoptotic process	1	56.7×	0.031	PIDD1
DNA damage response	1	53.5×	0.031	PIDD1
intracellular signal transduction	1	38.1×	0.036	PIDD1
negative regulation of apoptotic process	1	34.8×	0.036	PIDD1
apoptotic process	1	28.7×	0.039	PIDD1
signal transduction	1	16.1×	0.062	PIDD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIDD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PIDD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PIDD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.